Myelin-associated glycoprotein (MAG) is a cell surface transmembrane molecule expressed on the surface of myelin consisting of five extracellular immunoglobulin domains, a single transmembrane domain and an intracellular domain. MAG expression is restricted to myelinating glial cells: oligodendrocytes in the central nervous system and Schwann cells in the peripheral nervous system. MAG interacts with neuronal receptor(s) which initiate bi-directional signalling between neurons and glia. The effect of MAG binding to neuronal receptors is known to result in inhibition of neurite outgrowth in vitro. Based on this in vitro data, antagonists of MAG have been postulated as useful for the promotion of axonal sprouting following injury (WO95/22344, WO97/01352 and WO97/07810), although these claims are not supported by in vivo data. WO02/062383 discloses that an anti-MAG antibody, when administered directly into the brain or intravenously following focal cerebral ischaemia in the rat (a model of stroke) provides neuroprotection and enhances functional recovery.
Evidence in the literature suggests that MAG also mediates signalling into glial cells, but the functional significance of this has not been understood. It has been reported that engagement of MAG expressed at the surface of a CHO cell using an antibody leads to the activation of fyn kinase (Umemori et al., 1994, Nature, 367, 572-576). Furthermore, MAG knockout animals exhibit defects in myelin which resemble aspects of the defective changes observed in the brains of multiple sclerosis and encephalomyelitis patients (Lassman et al., Glia, 19, 104-110).
In animals, neutralisation of MAG following neuronal injury has been shown to promote regeneration in peripheral and central nerves (Torigoe et al., Experimental Neurology. 1998, 150:254-262; Mears et al., Journal of the Peripheral Nervous System. 2003, 8:91-99). Data from pre-clinical studies demonstrate that promotion of regeneration following neuronal injuries can enhance recovery (Lee et al., J Neuroscience, 2004, 24(27):6209-6217; GrandPre et al., Nature, 2002, 417(6888):547-551). In stroke patients, there is continued loss of neurons in the penumbra as shown by 11C-Flumazenil PET (Guadagno et al., Brain, 2008, 131:2666-2678). In rats with stroke induced by MCAO, MAG expression (mRNA and protein) is significantly upregulated in the peri-infarct area for several weeks after MCAO (Li et al., Neurobiology of Disease, 2006, 23:362-373). It is hypothesized that this over-expression of MAG may, at least in part, account for the continued loss of neurons and failure of neuro-regeneration after stroke.
PCT application PCT/EP2004/001016 (published as WO2004/083363 A2) discloses a method of promoting oligodendrocyte survival in a human suffering or at risk of developing stroke or another neurological disease which comprises administering to said human a therapeutically effective amount of an anti-MAG antibody or a functional fragment thereof.
PCT application PCT/EP2003/008749 (published as WO2004/014953 A2) discloses altered antibodies to myelin associated glycoprotein, pharmaceutical compositions containing them and to the use of such antibodies in the treatment and/or prophylaxis of neurological diseases/disorders, such as stroke.
PCT application PCT/GB2002/000551 (published as WO2002/062383 A2) discloses a method of treatment of neurological diseases and antibodies for use in such method.
Irving et al., J. Cerebral Blood Flow & Metabolism, “Identification of neuroprotective properties of anti-MAG antibody: a novel approach for the treatment of stroke?”, 2005, 24, 98-107 relates to a commercially available anti-MAG antibody administered either intracerebrally at 1, 24 or 72 hours post-MCAO in the rat, or intravenously at 1 and 24 hours post-MCAO.
Grundy et al., J. Cerebral Blood Flow & Metabolism, “Functional recovery and increased PSA-NCAM expression following delayed administration of an anti-MAG antibody post stroke in the rat, 2005, 25, S233 related to two doses of a commercially available anti-MAG antibody administered intracerebroventirularly 24 hours apart, starting at 1, 6 or 24 hours following tMCAO.
Dr Steve Cramer presented a poster, entitled “A single-blind Study of the Safety, Pharmacokinetics, and Pharmacodynamics of Escalating Repeat Doses of GSK249320 in Patients with Stroke” at the 2010 International Stroke Conference (23-25 Feb. 2010) held in San Antonio, Tex. and hosted by the American Stroke Association.